Closed Loop and Education for Hypoglycemia Awareness Restoration

The purpose of the CLEAR study is to determine the effect on counterregulatory responses (CRR) of intervening (by attempting to strictly avoid hypoglycemia) to improve awareness of hypoglycemic symptoms among adults with type 1 diabetes (T1D) who have impaired awareness of hypoglycemia (IAH). IAH affects 20-25% of adults with T1D, and rises with increasing duration of T1D.

Individuals with IAH exhibit blunted symptomatic and CR hormonal responses to hypoglycemia and, as such, have an impaired ability to respond to hypoglycemia. Thus, rates of severe hypoglycemia are up to 6-fold greater in those affected. Intensive management of T1D is necessary in preventing long-term complications, but can be complicated by recurrent episodes of hypoglycemia which lead to and sustain the CRR deficits of IAH. Technologies such as continuous glucose monitoring (CGM) and hybrid closed-loop (HCL) systems can reduce severe hypoglycemia (and also may reduce IAH) but the ability of technology to reverse impaired CRR (as assessed with experimental hypoglycemia clamp) remains unclear. Behavioral and psycho-educational interventions targeting knowledge/skills gaps, as well as particular cognitions and behaviors driving recurrent hypoglycemia, can also reduce severe hypoglycemia and improve awareness. No studies have compared technology with such behavioral interventions in terms of assessing their impact on IAH or the CRR (as a primary outcome). Unanswered questions include the degree of reduction in hypoglycemia required to restore awareness. Furthermore, participants may respond to different interventions according to their characteristics. For example, it remains unclear whether older individuals benefit from such interventions since they usually are excluded from studies. Therefore, there is an urgent need to determine effective interventions that can reverse IAH in a large representative population of adults with T1D and IAH. The investigators propose to study the effect of specific interventions aimed at restoring * the CRR (tested via an experimental hypoglycemia clamp procedure) * hypoglycemia awareness (self-reported via the Towler Questionnaire during the experimental hypoglycemia clamp procedure) The study will use a Sequential Multiple Assignment Randomized Trial (SMART) design. At baseline, all participants who are HCL naïve will be randomized to HCL or Usual Care (UC) plus brief education (My HypoCOMPaSS) with a follow-up of two years. UC will consist of real-time continuous glucose monitoring (CGM) and insulin delivery via pump or multiple daily injections. Participants who fail to increase their CRR at 12 months will be randomized, or assigned, to a second intervention consisting of a small-group educational program focusing on motivations and unhelpful cognitions acting as barriers to hypoglycemia avoidance (HARPdoc). At baseline, all participants who are HCL non-naïve will be randomized to optimized HCL or HCL plus My HypoCOMPaSS; those with non-responsive CRR at 12 months will be randomized to either continue HCL (on the basis they need a longer period to reverse impaired CRR and total symptomatic responses) or to the HARPdoc intervention. Participants randomized to an HCL device are expected to wear the device continually, as well as a CGM. The My HypoCOMPaSS education requires 4-5 hours of training, whereas, the HARP trial.show_full_description

Inclusion Criteria: * Clinical diagnosis of type 1 diabetes * Gold Score or Clarke Score ≥ 4 (highly associated with IAH) * Random non-fasting C-peptide \< 200 pmol/L * Diabetes duration ≥ 10 years * HbA1c \< 10.5% * Total Daily Insulin Dose of \< 1 unit/kg * Ability to read and speak English (because validated non-English versions of the cognitive tests and the educational interventions are not available) Exclusion Criteria: * Medical conditions that limit participation in study activities, as determined by the PI (including but not limited to cognitive dysfunction, reduced hearing, reduced vision, cancer under active treatment, untreated angina, organ failure) * Active alcohol or drug abuse (as defined by DSM criteria of either 1) recurrent use of alcohol/drugs resulting in a failure to fulfill major role obligations at work, school, or home, 2) recurrent alcohol/drug use in situations in which it is physically hazardous, or 3) recurrent alcohol or drug-related legal problems) * Social determinants of health that limit participation in study activities, as determined by the PI (including but not limited to homelessness, food insecurity, inadequate social support) * Seizure disorder unrelated to hypoglycemia associated seizures, unless documented seizure-free for \>12 months and on a stable regimen of anti-convulsant therapy * Skin conditions that would preclude the use of a CGM * Super-physiologic exposure to steroids within one month of enrollment * eGFR \< 45 mL/min/1.73 m2 * History of bariatric surgery that irreversibly alters gut innervation and structure * Hyper- or hypokalemia (serum potassium \>5.5 or \<3.5 mmol/L)\* * Hemoglobin \< 10 g/dL\* * Medical condition that requires intermittent or continuous use of glucocorticoids at greater than physiological replacement doses * Pregnancy, plan for pregnancy, or breast feeding * Abnormal thyroid function tests of clinical significance, as determined by PI\* * Liver transaminases \> 3 times the upper limit of normal\* * Hospitalization for mental illness in last year * History of adrenalectomy * At discretion of the PI, laboratory tests may be repeated once. If the participant is not eligible after the second attempt, then the participant. The participant may be screened again.